Advances and challenges in regenerative therapies for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a significant source of mortality worldwide and carries a mortality of greater than 80% after rupture. Despite extensive efforts to develop pharmacological treatments, there is currently no effective agent to prevent aneurysm growth and rupture. Current treatment paradigms only rely on the identification and surveillance of small aneurysms, prior to ultimate open surgical or endovascular repair. Recently, regenerative therapies have emerged as promising avenues to address the degenerative changes observed in AAA. This review briefly outlines current clinical management principles, characteristics, and pharmaceutical targets of AAA. Subsequently, a thorough discussion of regenerative approaches is provided. These include cellular approaches (vascular smooth muscle cells, endothelial cells, and mesenchymal stem cells) as well as the delivery of therapeutic molecules, gene therapies, and regenerative biomaterials. Lastly, additional barriers and considerations for clinical translation are provided. In conclusion, regenerative approaches hold significant promise for in situ reversal of tissue damages in AAA, necessitating sustained research and innovation to achieve successful and translatable therapies in a new era in AAA management.

Efficacy and safety of sonographer discretion to terminate a venous duplex ultrasound for diagnosis of deep vein thrombosis in coronavirus disease 2019 patients.

OBJECTIVE: Sonographers performing venous duplex ultrasound (VDUS) of patients with coronavirus disease 2019 (COVID-19) have an increased risk of exposure owing to their close contact with these patients for an extended period. The objective of the present study was to evaluate the efficacy of a modified COVID-19 VDUS protocol to reduce sonographer exposure to COVID-19 patients. METHODS: We performed a single-center retrospective review. Patients who had undergone VDUS under the modified COVID-19 protocol between March 1, 2020, and June 30, 2020, with a confirmed or presumed COVID-19 diagnosis at the VDUS were included. The modified COVID-19 protocol was defined as the ability of the sonographer to terminate the examination on detection of an acute deep vein thrombosis (DVT). The primary outcome measures were the number of anatomic deep venous segments recorded by the sonographer, which was used as a surrogate measure for sonographer exposure time, and the number of acute DVTs found on follow-up examinations in segments not visualized at the index VDUS. RESULTS: A total of 160 lower extremity VDUS (LEVDUS) scans and 72 upper extremity VDUS (UEVDUS) scans were performed using the modified COVID-19 protocol. The index VDUS had found an acute DVT for 44 of 160 patients (27.5%) who had undergone LEVDUS and 26 of 72 (36.6%) who had undergone UEVDUS. On follow-up imaging, 7 of 38 LEVDUS scans (17.9%) and 1 of 10 UEVDUS scans (10%) had demonstrated a new acute DVT. Malignancy and surgery 30 days before imaging were significantly associated with acute lower extremity DVT, and mechanical ventilation and extracorporeal membrane oxygenation were associated with acute upper extremity DVT. On the index VDUS, the average was 10.6 of 12 total visualized segments on LEVDUS and 6.4 of 10 total segments on UEVDUS. Of the index VDUS scans, 35.6% of the LEVDUS and 78.6% of the UEVDUS scans had been abbreviated. The index VDUS scans that were positive for acute DVT had had significantly fewer visualized segments for both lower (8.4 vs 11.5; P < .0001) and upper (4.2 vs 7.6) extremities (P < .0001). On the follow-up examinations, only one of eight new acute DVTs had been found in a patient whose index VDUS had been abbreviated and the corresponding segment not assessed. These findings did not affect the patient's clinical course. CONCLUSIONS: The modified COVID-19 VDUS protocol reduced sonographers' potential exposure time to COVID-19. Additionally, the clinical efficacy was maintained, with no missed DVTs, despite the abbreviation of the VDUS examinations.

Challenges and opportunities associated with the MD Anderson IMPACT2 randomized study in precision oncology.

We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient's/physician's choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.

Patient-specific meta-analysis of 12-gene colon cancer recurrence score validation studies for recurrence risk assessment after surgery with or without 5FU and oxaliplatin.

Background: Individualized estimates of the risk of recurrence in colon cancer patients are needed that reflect current medical practice and available treatment options. Methods: Three validation studies of the 12-gene colon recurrence score assay were used with pre-specified patient-specific meta-analysis (PSMA) methods to integrate the 12-gene Oncotype DX Colon Recurrence Score result (RS) with the clinical and pathology risk factors stage, T-stage, mis-match repair (MMR) status, and number of nodes examined to calculate individualized recurrence risk estimates. Baseline risk estimation used the most recent studies, so the risk estimates reflect current medical practice. The effect of fluorouracil (5FU) was estimated with a meta-analysis of two studies. The effect of oxaliplatin was estimated using one of the RS assay validation studies, in which patients were randomized to 5FU with or without oxaliplatin. Results: The RS result and each of the clinical-pathologic factors provided independent prognostic information for recurrence. Among stage II, T3, MMR-proficient patients with ≥12 nodes examined (the most common scenario), patients with RS ≤30 (approximately 48%) have estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-deficient patients with ≥12 nodes examined, patients with RS ≤19 (approximately 14%) have an estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-proficient patients with ≥12 nodes examined, those with RS ≤14 (approximately 6%) have estimated 5-year recurrence risk ≤10% with 5FU alone. Discussion: The PSMA integrates the 12-gene colon RS result with clinical and pathology factors to provide individualized recurrence risk estimates that reflect current medical practice. The risk estimates are in a range that may help inform treatment decisions for a substantial number of stage II and stage III patients.

Changes in Anesthesia Can Reduce Periprocedural Urinary Retention After EVAR.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs provide a streamlined approach for expedient postoperative care of high-volume procedures. Endovascular aortic repair (EVAR) has become standard treatment for abdominal aortic aneurysms and implementation of an early recovery program is warranted. Postoperative urinary retention (POUR) remains a problem lending to longer hospital stays and patient discomfort. We aim to demonstrate the utility of monitored anesthetic care (MAC) plus local anesthesia as a modality to minimize urinary retention following EVAR. METHODS: Single-center retrospective review from January 2017 to March 2020 of all patients undergoing standard elective EVAR under general anesthesia or MAC anesthesia. Local anesthetic at vessel access sites was used in all patients under MAC. Ruptured pathology and female sex were excluded from analysis. Patient characteristics, operative details, prostate measurements, and outcomes were abstracted from the electronic medical record. Urinary retention was defined as any requirement of straight catheterization, urinary catheter replacement, or discharge with urinary catheter. Chi square tests and logistic regression were used to determine predictors associated with POUR and increased hospital length of stay. RESULTS: Among 138 patients who underwent EVAR, eight (5.8%) were excluded due to ruptured pathology. Of the cohort, 113 (86.9%) were male with mean age of 73 years. Excluding female patients, 63 (55.8%) male patients underwent general anesthesia and 50 (44.3%) underwent MAC. Male patients under general anesthesia were more likely to have intra-operative urinary catheter placement when compared to MAC (82.5% vs. 36%, respectively; P < 0.001). POUR was identified in 17 patients (13.1%) of the entire study population with 15 events (88.2%) occurring in males. Excluding patients who were admitted to the ICU, twenty-two (19.5%) male patients stayed past postoperative day (POD) one, of which those who developed POUR were more likely to experience compared to those without POUR (45.6% vs. 9.7%, respectively; P = 0.001). On multivariable analysis, male patients who received MAC had a lower risk of developing POUR (OR 0.09, 95% CI 0.02-0.50). POUR was not associated with elective urinary catheter placement nor with pre-existing conditions such as diabetes, urinary retention, benign prostatic hypertrophy (BPH), or use of BPH medications. Additionally, neither prostate size nor volume was associated with developing POUR among male patients. CONCLUSION: MAC plus local anesthesia is associated with decreased rates of POUR after elective EVAR in male patients. ERAS pathways during elective EVAR interventions should implement MAC plus local anesthesia as an acceptable anesthetic option, where appropriate, in order to reduce urinary retention rates and subsequently decrease hospital length of stay in this patient cohort.

Direct oral anticoagulants decrease treatment failure for acute lower extremity deep venous thrombosis.

OBJECTIVE: Optimal medical therapy for acute lower extremity deep venous thrombosis (DVT) remains an enigma. While clinical trials demonstrate non-inferiority with an oral anti-Xa inhibitor, or direct oral anticoagulant (DOAC), versus combined low-molecular weight heparin (LMWH) and oral vitamin K antagonist (VKA), the most effective regimen remains to be determined. METHODS: This study is a single-center retrospective cohort study from October 2014 to December 2015 of patients with a diagnosis of acute DVT and subsequent serial lower extremity venous duplex. Demographics, medical history, medications, serial ultrasound findings, as well as the primary anticoagulant used for treatment were collected and analyzed by two independent data extractors. Treatment failure was defined as any new DVT or progression of an existing DVT within 3 months of diagnosis of the index clot. Risk factors for treatment failure were assessed using standard odds ratios and Fischer's exact test. RESULTS: Among 496 patients with an acute lower extremity DVT, 54% (n = 266) were men, mean age was 61 years, 35% (n = 174) involved the popliteal or more proximal segments, and 442 had documentation of the primary treatment for DVT: 20% (n = 90) received nothing; 20% (n = 92) received an oral VKA; 34% (n = 149) received a DOAC; 20% (n = 90) received LMWH; and 5% (n = 21) received another class of anticoagulant. Within 3 months, 21% (n=89 out of 427) had treatment failure defined as any new DVT or progression of prior DVT. Patients treated with a DOAC were less likely to experience treatment failure when compared with any other treatment (odds ratio 0.43; 95% confidence intervals [0.23, 0.79]; p = 0.0069) and when compared with traditional oral VKA (OR 0.44; 95% CI [0.21, 0.92]; p = 0.029). None of prior history of DVT, pulmonary embolism, thrombophilia, renal insufficiency, hepatic insufficiency, cancer, or antiplatelet therapy correlated with treatment failure. Treatment outcome did not correlate with being on any anticoagulation versus none (p = 0.74), nor did it correlate with the duration of treatment (<3 months versus ≥3 months) (p = 0.42). Proximal and distal DVTs showed no difference in treatment failure (19% versus 22%, respectively; p = 0.43). CONCLUSION: In summary, the use of a DOAC for acute lower extremity DVT yielded better overall outcomes and fewer treatment failures at 3 months as compared to traditional oral VKA therapy based on serial duplex imaging.

Practice-Changing Use of the 21-Gene Test for the Management of Patients With Early-Stage Breast Cancer in Latin America.

PURPOSE: We present a physician survey of the impact of 21-gene Breast Recurrence Score test results on treatment decisions in clinical practice in Latin America. METHODS: This prospective survey enrolled consecutive patients at 14 sites in Argentina, Colombia, Mexico, and Peru who had routine 21-gene testing. Physician surveys captured patient and tumor characteristics and treatment decisions before and after 21-gene test results. The survey spanned the period before and after Trial Assigning Individualized Options for Treatment (TAILORx) results reported (June 2018). Overall net percent change in adjuvant chemotherapy recommendations was estimated, and asymptotic 95% CIs with continuity correction were calculated. The proportion with a change between pretest treatment recommendation and actual treatment received was calculated overall and by Recurrence Score groups per TAILORx. RESULTS: Between March 2015 and December 2019, the survey was completed for 647 patients; 20% were node-positive. The mean patient age was 54 years (24-85 years); 55% were postmenopausal; 17%, 63%, and 20% had grade 1, 2, and 3 tumors, respectively; and 30% had tumors > 2 cm. Recurrence Score (RS) results were as follows: 20% RS 0-10, 56% RS 11-25, and 24% RS 26-100. Overall, chemotherapy recommendations fell by a relative proportion of 39% (95% CI, 33.4 to 44.3) after 21-gene testing (33% decrease in node-negative and 55% decrease in node-positive). Among node-negative patients, the relative decrease in chemotherapy recommendations was 28% (95% CI, 18.9 to 39.5) before TAILORx and 36% (95% CI, 28.4 to 43.7) after. CONCLUSION: To our knowledge, this large survey of 21-gene test practice patterns was the first conducted in Latin America and showed the relevance of 21-gene testing in low- and medium-resource countries to minimize chemotherapy overuse and underuse in breast cancer. The results showed substantial reductions in chemotherapy use overall-especially after TAILORx reported-indicating the practice-changing potential of that study.

Substantial Reduction in Adjuvant Chemotherapy With the Use of the 21-Gene Test to Manage Early Breast Cancer in a Public Hospital in Brazil.

PURPOSE: We evaluated the impact of 21-gene test results on treatment decisions for patients with early-stage breast cancer treated under the public health care system in Brazil, Sistema Único de Saúde. METHODS: Eligible patients treated at Hospital Pérola Byington and Santa Casa de Misericórdia de São Paulo in Brazil were required to have the following characteristics: postsurgery with hormone receptor-positive, human epidermal growth factor 2-negative, node-negative and node-positive, and T1/T2 breast cancer and patients with these characteristics were candidates for adjuvant systemic therapy. Treatment recommendations, chemotherapy plus hormonal therapy (CT + HT) or HT alone, were captured before and after 21-gene test results. RESULTS: From August 2018 to April 2019, 179 women were enrolled. The mean age was 58 years (29-86 years), 135 (76%) were postmenopausal, and 58 (32%) had node-positive breast cancer. Most patients (61%) had a tumor > 2 cm, including 7% with tumors > 4 cm. Using Recurrence Score (RS) result cut points on the basis of the TAILORx trial, 40 (22%) had RS 0-10, 91 (51%) had RS 11-25, and 48 (27%) had RS 26-100. Before 21-gene testing, 162 of 179 (91%) patients were recommended for CT. After testing, 117 of 179 patients (65%) had changes in CT recommendation: 112 (63%) who were initially recommended CT received HT alone and five (3%) who were initially recommended HT alone received CT + HT. After 21-gene testing, 99% of physicians reported strong confidence in their treatment recommendations. CONCLUSION: The change in clinical practice at these public hospitals was greater than expected: 66% of initial treatment recommendations were changed to omit CT with 21-gene test results. Clinicopathologic features did not correlate well with 21-gene test results and did not adequately identify those most likely to benefit from CT.

Assessment of the Accuracy and Reliability of Vascular Surgery Quality Metrics.

BACKGROUND: Health care quality metrics are crucial to medical institutions, payers, and patients. Obtaining current and reliable quality data is challenging, as publicly reported databases lag by several years. Vizient Clinical Data Base (previously University Health Consortium) is utilized by over 5,000 academic and community medical centers to benchmark health care metrics with results based on predetermined Vizient service lines. We sought to assess the accuracy and reliability of vascular surgery service line metrics, as determined by Vizient. METHODS: Vizient utilizes encounter data submitted by participating medical centers and generates a diverse array of health care metrics ranging from mortality to costs. All inpatient cases captured by Vizient under the vascular surgery service line were identified at the University of Massachusetts Medical Center (fiscal year 2016). Each case within the service line was reviewed and categorized as "vascular" or "nonvascular" based on care provided by UMass vascular surgery faculty: vascular = vascular surgery was integral part of care, nonvascular = vascular surgery had minimal or no involvement. Statistical analysis comparing length of stay (LOS), cost, readmission, mortality, and complication rates between vascular and nonvascular cohorts was performed. All inpatient cases discharged by a vascular surgeon National Provider Identifier number were also reviewed and categorized according to Vizient service lines. RESULTS: Vizient's vascular surgery service line identified 696 cases, of which 556 (80%) were vascular and 140 (20%) were nonvascular. When comparing these 2 cohorts, vascular cases had a significantly lower LOS (3.4 vs. 8.7 days; P < 0.0001), cost ($8,535 vs. $16,498; P < 0.0001), and complication rate (6.5% vs. 18%; P < 0.0001) than nonvascular. Mortality was also lower (1.6% vs. 5.7%; P < 0.01), but after risk-adjustment, this difference was not significant. When discharging vascular surgeon National Provider Identifier was used to identify vascular surgery cases, only 69% of these cases were placed within the vascular surgery service line. CONCLUSIONS: Health care quality metrics play an important role for all stakeholders but obtaining accurate and reliable data to implement improvements is challenging. In this single institution experience, inpatient cases that were not under the direction or care of a vascular surgeon resulted in significantly negative impacts on LOS, cost, complication rate, and mortality to the vascular surgery service line, as defined by a national clinical database. Therefore, clinicians must understand the data abstracting and reporting process before implementing effective strategic plans.

Correction to: Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial.

The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial, written by Ulrike Nitz, Oleg Gluz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Wolfram Malter, Benno Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Andrea Stefek, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne Just, Doris Augustin, Cornelia Liedtke, Calvin Chao, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe, Nadia Harbeck, was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 29, 2017 without open access.With the author(s)' decision to opt for Open Choice the copyright of the article changed on January 6, 2019 to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/ ), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated. The original article has been corrected.

Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study.

PURPOSE: The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole. METHODS: NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS < 18 versus RS ≥ 31. Secondary endpoints included evaluation of clinical response and rate of breast-conserving surgery (BCS) by continuous Recurrence Score result, ESR1 and PGR single-gene scores, and ER gene-group score. RESULTS: Of 295 TransNEOS patients (median age 63 years; median tumor size 25 mm; 66% grade 1), 53.2% had RS < 18, 28.5% had RS18-30, and 18.3% had RS ≥ 31. Clinical response rates were 54% (RS < 18), 42% (RS18-30), and 22% (RS ≥ 31). A higher proportion of patients with RS < 18 had clinical responses (p < 0.001 vs. RS ≥ 31). In multivariable analyses, continuous Recurrence Score result (p < 0.001), ESR1 score (p = 0.049), PGR score (p < 0.001), and ER gene-group score (p < 0.001) were associated with clinical response. Recurrence Score group was significantly associated with rate of BCS after neoadjuvant treatment (RS < 18 vs. RS ≥ 31, p = 0.010). CONCLUSION: The Recurrence Score test is validated to predict clinical response to neoadjuvant letrozole in postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer.

Robot-Assisted Thoracoscopic Resection of a Posterior Mediastinal Mullerian Cyst.

First described in 2005, the Mullerian derived cyst in the mediastinum is a rare finding with few subsequent reports. We report a case of Mullerian cyst occurring in the mediastinum of a 49-year-old female that was resected by robot-assisted thoracoscopic surgery. To our knowledge, this is the first report of robot-assisted resection of Hattori's cyst. Histopathologic analysis revealed ciliated Mullerian-type tubal epithelium positive for paired box gene 8 (PAX8), estrogen receptor (ER), and progesterone receptor (PR), confirming Mullerian differentiation. We also review the clinical presentation, pathology, and differential diagnosis of such cysts.

Prospective Evaluation of the Impact of the 21-Gene Recurrence Score Assay on Adjuvant Treatment Decisions for Women with Node-Positive Breast Cancer in Ontario, Canada.

BACKGROUND: The 21-gene Recurrence Score (RS) assay is only reimbursed in Ontario for node-negative and micrometastatic node-positive (N+) early-stage breast cancer (EBC). We carried out a prospective study to evaluate the impact of the assay on treatment decisions for women with N+ EBC. SUBJECTS, MATERIALS, AND METHODS: Women with estrogen receptor-positive, human epidermal growth receptor 2-negative EBC and one to three positive axillary lymph nodes, who were candidates for adjuvant chemotherapy in addition to hormonal treatment, but in whom the benefit of chemotherapy was uncertain, were eligible. The primary objective was to characterize how the results of the RS assay affected physicians' recommendations for adjuvant chemotherapy. Secondary objectives were to characterize changes in the physicians' and patients' level of confidence in treatment recommendations, to determine whether the results of the RS assay affected patients' treatment preferences, and to determine the final treatment administered. RESULTS: Seventy-two patients were recruited; the mean age was 61. RS was <18 in 55%, between 18 and 30 in 36%, and ≥31 in 9% of patients. Treatment recommendations changed in 36% of all evaluable patients. The most significant change was in the group with a low RS. Physicians' and patients' confidence in treatment recommendations increased in 49% and 54% of cases, respectively. Upfront chemotherapy was recommended to 79% of patients before the assay; 42% ultimately received chemotherapy. CONCLUSION: The RS assay resulted in a substantial decrease in the number of patients who received chemotherapy and in an increase in physicians' and patients' confidence in the adjuvant treatment recommendations. IMPLICATIONS FOR PRACTICE: This is the first decision impact study to include exclusively women with ER-positive, HER2-negative, early-stage breast cancer with 1-3 positive lymph nodes, a population typically treated with adjuvant chemotherapy. This study provides evidence that, in these patients, the Oncotype Dx Recurrence Score assay influences systemic treatment decisions. Most of the changes in treatment recommendation resulted in withdrawal of chemotherapy or change in recommendation from a chemotherapy regimen with anthracyclines to a taxane-only regimen. If prospective studies confirm that these decisions result in good outcomes, a reduction in the use of chemotherapy might result in pharmacoeconomic savings.

Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial.

BACKGROUND: The prospective phase 3 PlanB trial used the Oncotype DX® Recurrence Score® (RS) to define a genomically low-risk subset of clinically high-risk pN0-1 early breast cancer (EBC) patients for treatment with adjuvant endocrine therapy (ET) alone. Here, we report five-year data evaluating the prognostic value of RS, Ki-67, and other traditional clinicopathological parameters. METHODS: A central tumour bank was prospectively established within PlanB. Following an early amendment, hormone receptor (HR)+ , pN0-1 RS ≤ 11 patients were recommended to omit chemotherapy. Patients with RS ≥ 12, pN2-3, or HR-negative/HER2-negative disease were randomised to anthracycline-containing or anthracycline-free chemotherapy. Primary endpoint: disease-free survival (DFS). PlanB Clinicaltrials.gov identifier: NCT01049425. FINDINGS: From 2009 to 2011, PlanB enrolled 3198 patients (central tumour bank, n = 3073) with the median age of 56 years, 41.1% pN+, and 32.5% grade 3 EBC. Chemotherapy was omitted in 348/404 (86.1%) eligible RS ≤ 11 patients. After 55 months of median follow-up, five-year DFS in ET-treated RS ≤ 11 patients was 94% (in both pN0 and pN1) versus 94% (RS 12-25) and 84% (RS > 25) in chemotherapy-treated patients (p < 0.001); five-year overall survival (OS) was 99 versus 97% and 93%, respectively (p < 0.001). Nodal status, central/local grade, tumour size, continuous Ki-67, progesterone receptor (PR), IHC4, and RS were univariate prognostic factors for DFS. In a multivariate analysis including all univariate prognostic markers, only pN2-3, central and local grade 3, tumour size >2 cm, and RS, but not IHC4 or Ki-67 were independent adverse factors. If RS was excluded, IHC4 or both Ki-67 and PR entered the model. The impact of RS was particularly pronounced in patients with intermediate Ki-67 (>10%, <40%) tumours. INTERPRETATION: The excellent five-year outcomes in clinically high-risk, genomically low-risk (RS ≤ 11) pN0-1 patients without adjuvant chemotherapy support using RS with standardised pathology for treatment decisions in HR+ HER2-negative EBC. Ki-67 has the potential to support patient selection for genomic testing.

Endocrine therapy initiation, discontinuation and adherence and breast imaging among 21-gene recurrence score assay-eligible women under age 65.

BACKGROUND: Aside from chemotherapy utilization, limited data are available on the relationship between gene expression profiling (GEP) testing and breast cancer care. We assessed the relationship between GEP testing and additional variables and the outcomes of endocrine therapy initiation, discontinuation and adherence, and breast imaging exams in women under age 65 years. METHODS: Data from five state cancer registries were linked with claims data and GEP results. We assessed variables associated with survivorship care outcomes in an incident cohort of 5014 commercially insured women under age 65 years, newly diagnosed with stage I or II hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2) non-positive breast cancer from 2006 to 2010. RESULTS: Among tested women, those with high Oncotype DX® Breast Recurrence Score® (RS) were significantly less likely to initiate endocrine therapy than women with low RS tumors (OR 0.40 (95% CI 0.20 to 0.81); P = 0.01). Among all test-eligible women, receipt of Oncotype DX testing was associated with a greater likelihood of endocrine therapy initiation (OR 2.48 (95% CI 2.03 to 3.04); P <0.0001). The odds of initiation were also significantly higher for tested vs. untested women among women who did not initiate chemotherapy within six months of diagnosis (OR 3.25 (95% CI 2.53 to 4.16)), with no effect in women who received chemotherapy. Discontinuation and adherence and breast imaging exams were unrelated to tested status or RS. CONCLUSIONS: Lower endocrine therapy initiation rates among women with high RS tumors and among untested women not receiving chemotherapy are concerning, given its established efficacy. Additional research is needed to suggest mechanisms to close this gap.

Prospective Evaluation of a 12-Gene Assay on Patient Treatment Decisions and Physician Confidence in Mismatch Repair Proficient Stage IIA Colon Cancer.

BACKGROUND: The Oncotype DX colon cancer assay is a validated predictor of recurrence risk in patients with resected stage II colon cancer. We previously reported that Oncotype DX led to a change in treatment recommendations for 45% of patients with T3 mismatch repair proficient (MMR-P) stage II tumors in a prospective study. In the present study, we report the assay's influence on patient treatment decisions, physician confidence, concordance between physicians and patients, and patient decisional conflict. PATIENTS AND METHODS: Consecutive patients with resected stage IIA colon cancer were enrolled. The tumor specimens were assessed using a 12-gene assay (reverse transcription-polymerase chain reaction) and by immunohistochemistry for MMR. Before and after receiving the results, the patients completed surveys that included their treatment preference, their current and preferred roles in treatment decision-making, and indicators of decisional conflict. Physicians completed similar pre- and postassay surveys. RESULTS: Of 221 patients enrolled, 139 T3 MMR-P patients were evaluable for the patient-reported analyses and 150 patients were evaluable for the physician-reported analyses. Before the assay, 46% of the patients chose observation, 3% 5-fluorouracil, 7% oxaliplatin, 4% other, and 41% were undecided. After the assay, 75% chose observation, 12% 5-fluorouracil, 11% oxaliplatin, and 2% other. After the assay, 94% of the defined treatment decisions were concordant between patients and physicians compared with 60% before the assay. Physicians reported the assay influenced their treatment decisions and increased confidence in their treatment recommendations for 69% and 84% of patients, respectively. Most patients (86%) reported that the assay influenced their treatment decisions. Patient decisional conflict was significantly lower after learning the assay results (P < .001). CONCLUSION: In the present prospective study, knowledge of the 12-gene assay results influenced treatment decisions for most patients and physicians, increased physician confidence, improved the concordance between patients and physicians, and decreased patient decisional conflict.

A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer.

BACKGROUND: African American (AA) colon cancer patients have a worse prognosis than Caucasian (CA) colon cancer patients, however, reasons for this disparity are not well understood. To determine if tumor biology might contribute to differential prognosis, we measured recurrence risk and gene expression using the Oncotype DX® Colon Cancer Assay (12-gene assay) and compared the Recurrence Score results and gene expression profiles between AA patients and CA patients with stage II colon cancer. METHODS: We retrieved demographic, clinical, and archived tumor tissues from stage II colon cancer patients at four institutions. The 12-gene assay and mismatch repair (MMR) status were performed by Genomic Health (Redwood City, California). Student's t-test and the Wilcoxon rank sum test were used to compare Recurrence Score data and gene expression data from AA and CA patients (SAS Enterprise Guide 5.1). RESULTS: Samples from 122 AA and 122 CA patients were analyzed. There were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median age was 66 years for AA patients and 68 for CA patients. Age, gender, year of surgery, pathologic T-stage, tumor location, the number of lymph nodes examined, lymphovascular invasion, and MMR status were not significantly different between groups (p = 0.93). The mean Recurrence Score result for AA patients (27.9 ± 12.8) and CA patients (28.1 ± 11.8) was not significantly different and the proportions of patients with high Recurrence Score values (≥41) were similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC and GADD45B), was significantly different between the racial groups. After controlling for clinical and pathologic covariates, the means and distributions of Recurrence Score results and gene expression profiles showed no statistically significant difference between patient groups. CONCLUSION: The distribution of Recurrence Score results and gene expression data was similar in a cohort of AA and CA patients with stage II colon cancer and similar clinical characteristics, suggesting that tumor biology, as represented by the 12-gene assay, did not differ between patient groups.

12-Gene Recurrence Score Assay Stratifies the Recurrence Risk in Stage II/III Colon Cancer With Surgery Alone: The SUNRISE Study.

PURPOSE: The 12-gene Recurrence Score assay has been validated in resected stage II colon cancer treated with or without chemotherapy and resected stage III disease treated with chemotherapy. This study evaluated the 12-gene Recurrence Score assay for stage II and III colon cancer without chemotherapy to reveal the natural course of recurrence risk in stage III disease. METHODS: A cohort-sampling design was used. From 1,487 consecutive patients with stage II to III disease who had surgery alone, 630 patients were sampled for inclusion with a 1:2 ratio of recurrence and nonrecurrence. Sampling was stratified by stage (II v III). The assay was performed on formalin-fixed, paraffin-embedded primary cancer tissue. Association of the Recurrence Score result with recurrence-free interval (RFI) was assessed by using weighted Cox proportional hazards regression. RESULTS: Overall, 597 of 630 patients were analyzable-247 patients had stage II, and 350 had stage III colon cancer. The continuous Recurrence Score was significantly associated with RFI after adjustment for disease stage (hazard ratio for a 25-unit increase in Recurrence Score, 2.05; 95% CI, 1.47 to 2.86; P < .001). With respect to prespecified subgroups, as defined by low (< 30), intermediate (30 to 40), and high (≥ 41) Recurrence Score risk groups, patients with stage II disease in the high-risk group had a 5-year risk of recurrence similar to patients with stage IIIA to IIIB disease in the low-risk group (19% v 20%), whereas patients with stage IIIA to IIIB disease in the high-risk group had a recurrence risk similar to that of patients with stage IIIC disease in the low-risk group (approximately 38%). CONCLUSION: To our knowledge, this study provides the first validation of the 12-gene Recurrence Score assay in stage III colon cancer without chemotherapy and showed the heterogeneity of recurrence risks in stage III as well as in stage II colon cancer.

The Impact of the Oncotype DX Breast Cancer Assay on Treatment Decisions for Women With Estrogen Receptor-Positive, Node-Negative Breast Carcinoma in Hong Kong.

BACKGROUND: The Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population. METHODS: Consecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured. RESULTS: A total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations. CONCLUSIONS: The Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong.